Improved synthesis of 15-deoxyspergualin analogs using the Ugi multi-component reaction.

Abstract

Spergualin is a natural product that exhibits immunosuppressive, anti-tumor and anti-bacterial activities. Its derivatives, such as 15-deoxyspergualin (15-DSG), have been clinically approved for acute allograft rejection. However, the reported syntheses are cumbersome (>10 steps) and they suffer from low overall yields (∼0.3% to 18%). Moreover, spergualin and its derivatives are chemically unstable and rapidly hydrolyzed in aqueous buffer. Here, we have re-explored these issues and report a modified synthetic route with significantly improved overall yield (∼31% to 47%). The key transformation is a microwave-accelerated Ugi multi-component reaction that is used to generate the peptoid core in a single step. Using the products of this route, we found that modifications of the hemiaminal significantly increased chemical stability. Thus, we anticipate that this synthetic route will improve access to biologically active 15-DSG derivatives.

• Authors: Christopher G Evans, Matthew C Smith, James P Carolan, Jason E Gestwicki
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 9 Pg. 2587-90 (May 01 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21420295 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Guanidines
• gusperimus

Topics

• Chemistry, Pharmaceutical
• Guanidines (chemical synthesis, chemistry)
• Molecular Structure